Murine myeloid leukemia M1 cells undergo terminal differentiation to mature macrophages after stimulation with interleukin-6 (IL-6). This process can be monitored by measuring the expression of early markers such as the high affinity receptor for monomeric IgG2a (FcgammaRI) and Ia antigen followed by the late markers such as lysozyme production and finally morphological changes from blast cells to mature macrophages. The same early markers that are expressed on M1 cells after induction with IL- 6 are also expressed on monocytic cells after activation with interferon- gamma (IFN-gamma). We used IL-6 and IFN-gamma to investigate whether the early stages of M1 cell differentiation could be accomplished without commitment of the cells to terminal differentiation. Cytofluorometry shows that the expression of the same early differentiation markers (FcgammaRI and Ia antigen) that are inducible by IL-6 on M1 cells can be induced by IFNgamma as well. However, stimulation with IFNgamma, in contrast to IL-6, does not induce the late differentiation markers such as lysozyme production, phagocytic activity, and morphological changes. Northern analysis supports these findings in that expression of FcgammaRI mRNA is induced by either cytokine, whereas expression of mRNA for lysozyme is inducible by IL-6 only. Nuclear run-on analysis reveals that the changes in steady state mRNA levels of both FcgammaRI and lysozyme are regulated by a transcriptional mechanisms. These data suggest that the early stages in the process of myeloid differentiation can be separately induced by IFN~and thus are independent from later events induced by IL-6. In addition to inducing differentiation in M1 cells, IL-6 is capable of inducing receptors to various cytokines which are not related directly to the differentiation process. We have previously shown that IL-6 induces the expression of membrane-bound interleukin-4 (IL-4) receptors (mIL-4R) in M1 cells as well as in bone marrow (BM)-derived mature macrophages. In the present study we show that IL-6 also induces the expression and secretion of the soluble form of the IL-4 receptor (sIL-4R) in these cells as well, with the protein accumulating for up to 72 hours in the cell supernatants. This inducible production of SIL-4R protein is accompanied by the induction of mRNA specific for the sIL-4R. In mature BM-derived macrophages data suggest that myeloid cells exposed to inflammatory stimuli, such as IL-6, are one possible source of sIL-4R. Thus, enabling myeloid cells can modulate the effects of IL-4 on immune responses by the regulating production of the soluble receptor for this cytokine.